Karina Dalsgaard Sørensen

Genetic predisposition to mosaic Y chromosome loss in blood

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Deborah J Thompson, Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge.
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  • Giulio Genovese, 1] Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA [2] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
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  • Jonatan Halvardson, Department of Immunology, Genetics and Pathology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
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  • Jacob C Ulirsch, Program in Genetics and Genomics, Biological and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts, USA.
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  • Daniel J Wright, Open Targets Core Genetics, Wellcome Sanger Institute, Hinxton, UK.
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  • Chikashi Terao, Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
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  • Olafur B Davidsson, deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
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  • Felix R Day, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands ; Department of Internal Medicine, Genetics Laboratory, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands.
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  • Patrick Sulem, deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
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  • Yunxuan Jiang, 23andMe, Inc., Mountain View, California, USA.
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  • Marcus Danielsson, Department of Immunology, Genetics and Pathology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
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  • Hanna Davies, Department of Immunology, Genetics and Pathology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
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  • Joe Dennis, Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge.
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  • Malcolm G Dunlop, Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit and CRUK Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK.
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  • Douglas F Easton, Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge.
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  • Victoria A Fisher, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland 20850, USA.
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  • Florian Zink, deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
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  • Richard S Houlston, Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SW7 3RP, UK.
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  • Martin Ingelsson, Geriatrics Research Group, Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden.
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  • Siddhartha Kar, Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK; Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
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  • Nicola D Kerrison, MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, United Kingdom.
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  • Ben Kinnersley, Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SW7 3RP, UK.
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  • Ragnar P Kristjansson, deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
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  • Philip J Law, Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SW7 3RP, UK.
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  • Rong Li, Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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  • Chey Loveday, Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SW7 3RP, UK.
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  • Jonas Mattisson, Department of Immunology, Genetics and Pathology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
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  • Steven A McCarroll, 1] Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA [2] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
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  • Yoshinori Murakami, Division of Molecular Pathology, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
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  • Anna Murray, Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter EX2 5DW, UK.
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  • Pawel Olszewski, Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland.
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  • Edyta Rychlicka-Buniowska, Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland.
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  • Robert A Scott, MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, United Kingdom.
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  • Unnur Thorsteinsdottir, 1] deCODE Genetics/Amgen, Inc., Reykjavik, Iceland. [2] Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
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  • Ian Tomlinson, Cancer Genetics and Evolution Laboratory, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
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  • Behrooz Torabi Moghadam, Department of Immunology, Genetics and Pathology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
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  • Clare Turnbull, William Harvey Research Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ UK.
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  • Nicholas J Wareham, MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, United Kingdom.
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  • Daniel F Gudbjartsson, 1] deCODE Genetics/Amgen, Inc., Reykjavik, Iceland. [2] School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
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  • Yoichiro Kamatani, Kyoto-McGill International Collaborative School in Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
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  • Eva R Hoffmann, DNRF Center for Chromosome Stability, Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
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  • Steve P Jackson, Wellcome Trust/Cancer Research UK Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, England, UK.
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  • Kari Stefansson, 1] deCODE Genetics/Amgen, Inc., Reykjavik, Iceland. [2] Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
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  • Adam Auton, 23andMe, Inc., Mountain View, California, USA.
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  • Ken K Ong, MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, United Kingdom.
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  • Mitchell J Machiela, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland 20850, USA.
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  • Po-Ru Loh, 1] Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA. [2] Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
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  • Jan P Dumanski, Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland.
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  • Stephen J Chanock, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland 20850, USA.
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  • Lars A Forsberg, Beijer Laboratory of Genome Research, Uppsala University, Uppsala, Sweden.
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  • International Lung Cancer Consortium (INTEGRAL-ILCCO)
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  • The PRACTICAL Consortium

Mosaic loss of chromosome Y (LOY) in circulating white blood cells is the most common form of clonal mosaicism1-5, yet our knowledge of the causes and consequences of this is limited. Here, using a computational approach, we estimate that 20% of the male population represented in the UK Biobank study (n = 205,011) has detectable LOY. We identify 156 autosomal genetic determinants of LOY, which we replicate in 757,114 men of European and Japanese ancestry. These loci highlight genes that are involved in cell-cycle regulation and cancer susceptibility, as well as somatic drivers of tumour growth and targets of cancer therapy. We demonstrate that genetic susceptibility to LOY is associated with non-haematological effects on health in both men and women, which supports the hypothesis that clonal haematopoiesis is a biomarker of genomic instability in other tissues. Single-cell RNA sequencing identifies dysregulated expression of autosomal genes in leukocytes with LOY and provides insights into why clonal expansion of these cells may occur. Collectively, these data highlight the value of studying clonal mosaicism to uncover fundamental mechanisms that underlie cancer and other ageing-related diseases.

Original languageEnglish
JournalNature
Volume575
Issue7784
Pages (from-to)652-657
Number of pages6
ISSN0028-0836
DOIs
Publication statusPublished - Nov 2019

    Research areas

  • Adult, Aged, Chromosome Deletion, Chromosomes, Human, Y/genetics, Computational Biology, Databases, Genetic, Female, Genetic Markers/genetics, Genetic Predisposition to Disease/genetics, Genomic Instability/genetics, Humans, Leukocytes/pathology, Male, Middle Aged, Mosaicism, Neoplasms/genetics, United Kingdom

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